Fungal pathogens are a worldwide threat to human health. Candida albicans, which is normally a commensal resident of the oral cavity, can cause oropharyngeal candidiasis (OPC) in individuals whose immune system is compromised by AIDS, chemotherapy, or use of immunosuppressant drugs. Histatins (Hsts) are a family of histidine-rich cationic proteins secreted by human major salivary glands that largely contribute to the antifungal activity of saliva. Hst 5 is strongly fungicidal in vitro, however its activity in sliva is substantially attenuated by proteolytic degradation as well as by other unknown factors. We identified C. albicans polyamine Dur transporters to be the conduit by which Hst 5 is translocated intracellularly, and designed an Hst 5 conjugated with the polyamine spermidine (Hst 54-15-Spd) that has superior uptake and killing properties. Hst 54-15-Spd appears to be resistant to salivary proteases and assumes a more unordered structure that may make it a better substrate for C. albicans Dur transporters. The basis for its proteolytic resistance and uptake kinetics will be examined in Aim 1. Various factors affect the outcome of antimicrobial therapy. These include the biological state of the pathogen and the availability of extraneous ligands such as metals outside the cell. C. albicans has three major signaling pathways that allow its adaptation to environmental stresses including Hst 5. We found that phosphorylation of Cek1 (P-Cek1) conditions cells to become more sensitive to Hst 5, a finding we will delineate and exploit as a combinatorial therapeutic in protective and treatment strategies in Aim 2. We found that iron, one of the most abundant metal in saliva, strongly binds Hst 5 and modifies its structure as well as reducing its killing activity. Intracellular Hst 5 may bind fungal cellular laile iron pools and redistribute its reserves, targeting it to the vacuoles and mitochondria, the two sites where Hst 5 accumulates. We propose that iron as well as other salivary metals have an unexplored role in modifying Hst 5 activity both in saliva as well as within the fungal cell that wll be examined in Aim 3